Uterine leiomyomas (ULs) are the most common pelvic tumors in women of reproductive age, accounting for over 600,000 hysterectomies annually in the United States. Several lines of evidence support a genetic liability in the pathogenesis of ULs, yet no susceptibility gene is known. Advances in research on the genetics of ULs (fibroids) have so far been limited by the paucity of genetic epidemiologic studies and infrastructure to conduct them. The goal of this epidemiologic study is to evaluate the contribution of a region of Chr.1q43 that predisposes to uterine fibroids but remains inadequately investigated. Genetic predisposition to ULs has been studied primarily in the context of two rare inherited autosomal-dominant conditions, the hereditary leiomyomatosis and renal cell cancer (HLRCC) and the multiple cutaneous and uterine leiomyomatosis (MCUL1) syndromes, where germline mutations were found in the gene on Chr. 1q43 encoding the tricaboxylic acid cycle (Krebs cycle) fumarate hydratase (FH) enzyme. However, a direct role of this important metabolic housekeeping gene in tumorigenesis remains to be proven. Inactivating FH mutations have rarely (< 1-2% of the tumors analyzed) been observed in nonsyndromic (common) ULs; however, loss of FH appears to be a significant event in the pathogenesis of a subset of these tumors. Furthermore, several observations support the existence of an alternative or additional candidate gene on Chr.1q43 acting alone or interacting with FH to increase the risk of ULs in susceptible individuals: 1) the absence of FH genotype-phenotype correlations, 2) the marked genetic heterogeneity in ULs, and 3) the failure to observe ULs or multiple leiomyomatosis in siblings or parents of cases with fumarase deficiency, a severe recessive disorder. Taken together, these observations underscore the importance of exploring an extended FH region in a population-based study of ULs. To this end, we will generate a high-density single nucleotide polymorphism genotyping data across a 2-Mb region spanning FH in subsets of African American (n=582) and Caucasian (n=455) women enrolled in the NIEHS-Uterine Fibroids Study. This is a well designed cross-sectional study of ULs that includes data on most potential confounders. Our study is not intended to shift any paradigm about the origins of ULs; rather it will extensively investigate the role of FH in nonsyndromic ULs, dissect the intricate genetic correlates of Chr.1q43 markers in the expression of the disease phenotype and evaluate their effects in two populations with a marked difference in disease risk. Recent updates in the genome databases have revealed new potential candidate genes for tumor growth and important structural variations including a large (~ 308 Kb) copy number variation in the vicinity of FH; these new findings further justify a study with the proposed depth and extent of genetic coverage. This study will likely open new avenues for research and may ultimately redirect current preventive and therapeutic approaches or enhance their efficacy. PUBLIC HEALTH RELEVANCE: Currently, the only effective and non-invasive therapy to treat uterine fibroids is a hormone (gonadotropin releasing hormone) - based therapy with serious side effects. The knowledge to be gained from this study could, at some point in the near future, lead to the development of the first genetic counseling protocol for fibroids and ultimately to a more appropriate therapy.